DESCRIPTION: Increased exposure to power frequency magnetic fields (EMF) has been proposed as a causal factor in the rising incidence of breast cancer in the United States. However, plausible biological mechanisms for the putative tumor enhancing effects of EMF at the level of the breast epithelial cell are essentially lacking. The overall hypothesis in the present application is that the effects of EMF on the breast are epigenetic in nature, and are effected through influences on the action of hormones and other regulators of breast epithelial cells and the non- transformed human breast epithelial cell strain HBL-100 as in vitro model systems, the proposed program will a) determine the influence of EMF + hormones on the proliferation of human breast epithelial cells; b) investigate alterations in expression of breast cancer- associated genes as a mechanism for EMF + hormone effects; and c) evaluate the role of local secondary electric fields and currents as mediators of EMF effects. Using an extensively validated in vitro EMF exposure system, initial studies will focus on the effects of EMF alone on cell proliferation and the expression of HER-2/neu, c-myc, p53, and cyclin E. Dose-response and time- response parameters will be determined to investigate a) the reversibility of induced effects, and b) the hypothesized existence of field strength "windows." After studies with EMF alone are completed, a series of addition and deletion experiments will be performed to study the interactions between EMF and estradiol, prolactin, and melatonin; these studies will be directed towards the identification of one or more endocrine mediators of EMF action in the breast. Additional experiments using annular ring plates will determine the importance of the secondary induction of electric fields and currents as mediators of the biological effects of EMF in the breast epithelium. Finally, should EMF be found to have no influence on the expression of the battery of breast cancer-associated genes heretofore evaluated, subtraction hybridization studies will be performed with sham- and EMF- exposed cells in order to identify genes other than HER-2/neu, c-myc, p53, and cyclin E whose expression is altered by EMF exposure. The results of these studies should identify one or more specific genes whose altered expression is associated with the proliferation of human breast epithelial cells, and will evaluate the role of endocrine status and the induction of local electric currents and fields as effectors of the biological activity of EMF. Several possible mechanisms of EMF action in the human breast epithelial cell will be evaluated in the proposed program. Should a biologically plausible mechanism for EMF action not be identified, the proposal that EMF exposure is causally related to human breast cancer is weakened considerably.